tbuckley/cabot-search huggingface dataset:
US Food and Drug Administration Accelerated Approval Program for Nononcology Drug Indications Between 1992 and 2018
Authors: Kenji Omae, Akira Onishi, Ethan Sahker, Toshi A. Furukawa
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The US Food and Drug Administration (FDA) grants accelerated approval according to surrogate measures of numerous drug indications for serious or life-threatening illnesses such as infectious diseases and cancer. Investigators, including the FDA, have evaluated the program's regulatory and clinical consequences in oncology, but evaluation of nononcology drugs is lacking. <h3>Objective</h3> To evaluate the accelerated approval program for nononcology drug indications over a period of 26 years. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used publicly available data on FDA nononcology drug indications granted accelerated approval from June 1992 through May 2018, with preapproval and confirmatory trials for approved drugs. Data were analyzed from February to April 2022. <h3>Main Outcomes and Measures</h3> The study estimated the median time from accelerated approval to occurrence of regulatory outcomes such as regular approval conversion, postapproval boxed warning label changes, confirmatory trial completion, and confirmatory trial results publication. <h3>Results</h3> The FDA granted accelerated approval of 48 drugs for 57 nononcology indications, including 23 (40%) HIV treatments, supported by 93 preapproval trials. Forty-three indications (75%) were converted to regular approval at a median time of 53.1 (95% CI, 38.7 to 70.2) months from accelerated approval. There were postapproval label modifications on boxed warnings in 27 indications (47%) with a median time of 248.6 (95% CI, 51.8 to not estimable) months from accelerated approval. Of the 86 required confirmatory trials, 17 (20%) had not fulfilled the postapproval requirements. The median time to confirmatory trial completion was 39.4 (95% CI, 30.7 to 47.9) months. Nine trials (10%) failed to verify clinical efficacy, but only 1 of 8 indications assessed (2%) was withdrawn owing to the failed confirmatory trial, which was 136 months after approval. Results were published in 56 completed confirmatory trials (65%), with the median time being 52.5 (95% CI, 35.6 to 82.2) months from accelerated approval to publication. <h3>Conclusions and Relevance</h3> Although the program expedited the approval of nononcology drug indications by a median (IQR) of 53.1 (26.8-133.2) months, safety-related label modifications were often added in boxed warnings after approval, and clinical efficacy was sometimes not confirmed. The study findings and long follow-up period suggest that comprehensive evaluation of such drugs may take more than a decade.
m6A-TSHub: Unveiling the Context-Specific m<b>6</b>A Methylation and m<b>6</b>A-Affecting Mutations in 23 Human Tissues
Authors: Bowen Song, Daiyun Huang, Yuxin Zhang, Zhen Wei, Jionglong Su, João Pedro de Magalhães, Daniel J. Rigden, Jia Meng, Kunqi Chen
Journal: Genomics Proteomics & Bioinformatics (2022)

As the most pervasive epigenetic marker present on mRNAs and long non-coding RNAs (lncRNAs), N
Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis
Authors: Rohit Loomba, Daniel Q. Huang, Arun J Sanyal, Quentin Mark Anstee, Michael Trauner, Eric J Lawitz, Dora Ding, Lily Ma, Catherine Jia, Andrew Billin, Ryan S Huss, Chuhan Chung, Zachary Goodman, Vincent Wai-Sun Wong, Takeshi Okanoue, Manuel Romero-Gómez, Manal F Abdelmalek, Andrew Muir, Nezam Afdhal, Jaime Bosch, Stephen Harrison, Zobair M Younossi, Robert P Myers
Journal: Gut (2022)

In retrospective studies, liver stiffness (LS) by vibration-controlled transient elastography (VCTE) is associated with the risk of liver decompensation in patients with non-alcoholic steatohepatitis (NASH), but prospective data in biopsy-confirmed cohorts with advanced fibrosis are limited. We aimed to establish thresholds for LS by VCTE that predict progression to cirrhosis among patients with bridging fibrosis and hepatic decompensation among patients with cirrhosis due to NASH.We used data from four randomised placebo-controlled trials of selonsertib and simtuzumab in participants with advanced fibrosis (F3-F4). The trials were discontinued due to lack of efficacy. Liver fibrosis was staged centrally at baseline and week 48 (selonsertib study) or week 96 (simtuzumab study). Associations between LS by VCTE with disease progression were determined using Cox proportional hazards regression analysis.Progression to cirrhosis occurred in 16% (103/664) of participants with bridging fibrosis and adjudicated liver-related events occurred in 4% (27/734) of participants with baseline cirrhosis. The optimal baseline LS thresholds were ≥16.6 kPa for predicting progression to cirrhosis, and ≥30.7 kPa for predicting liver-related events. Baseline LS ≥16.6 kPa (adjusted HR 3.99; 95% CI 2.66 to 5.98, p<0.0001) and a ≥5 kPa (and ≥20%) increase (adjusted HR 1.98; 95% CI 1.20 to 3.26, p=0.008) were independent predictors of progression to cirrhosis in participants with bridging fibrosis, while baseline LS ≥30.7 kPa (adjusted HR 10.13, 95% CI 4.38 to 23.41, p<0.0001) predicted liver-related events in participants with cirrhosis.The LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis.
ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants
Authors: Jeremy S. Nayagam, Rebecca Jeyaraj, Pierre Foskett, Anil Dhawan, Aftab Ala, Deepak Joshi, Adrian Bomford, Richard J. Thompson
Journal: Clinical Gastroenterology and Hepatology (2022)

Although a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants.This was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators.Of 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7-17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7-18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03).Patients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.
Early deaths associated with community-acquired and healthcare-associated bloodstream infections: a population-based study, Finland, 2004 to 2018
Authors: Keiju SK Kontula, Kirsi Skogberg, Jukka Ollgren, Asko Järvinen, Outi Lyytikäinen
Journal: Eurosurveillance (2022)

BackgroundBloodstream infections (BSI) cause substantial morbidity and mortality.AimWe explored the role of causative pathogens and patient characteristics on the outcome of community-acquired (CA) and healthcare-associated (HA) BSI, with particular interest in early death.MethodsWe used national register data to identify all BSI in Finland during 2004-18. We determined the origin of BSI, patients´ underlying comorbidities and deaths within 2 or 30 days from specimen collection. A time-dependent Cox model was applied to evaluate the impact of patient characteristics and causative pathogens on the hazard for death at different time points.ResultsA total of 173,715 BSI were identified; 22,474 (12.9%) were fatal within 30 days and, of these, 6,392 (28.4%) occurred within 2 days (7.9 deaths/100,000 population). The 2-day case fatality rate of HA-BSI was higher than that of CA-BSI (5.4% vs 3.0%). Patients who died within 2 days were older than those alive on day 3 (76 vs 70 years) and had more severe comorbidities. Compared with other BSI, infections leading to death within 2 days were more often polymicrobial (11.8% vs 6.3%) and caused by Pseudomonas aeruginosa (6.2% vs 2.0%), fungi (2.9% vs 1.4%) and multidrug-resistant (MDR) pathogens (2.2% vs 1.8%), which were also predictors of death within 2 days in the model.ConclusionsOverrepresentation of polymicrobial, fungal, P. aeruginosa and MDR aetiology among BSI leading to early death is challenging concerning the initial antimicrobial treatment. Our findings highlight the need for active prevention and prompt recognition of BSI and appropriate antimicrobial treatment.
A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer
Authors: Henrik Schinke, Enxian Shi, Zhongyang Lin, Tanja Quadt, Gisela Kranz, Jiefu Zhou, Hongxia Wang, Julia Hess, Steffen Heuer, Claus Belka, Horst Zitzelsberger, Udo Schumacher, Sandra Genduso, Kristoffer Riecken, Yujing Gao, Zhengquan Wu, Christoph A. Reichel, Christoph Walz, Martin Canis, Kristian Unger, Philipp Baumeister, Min Pan, Olivier Gires
Journal: Molecular Cancer (2022)

Abstract Background Epidermal growth factor receptor (EGFR) is both a driver oncogene and a therapeutic target in advanced head and neck squamous cell carcinoma (HNSCC). However, response to EGFR treatment is inconsistent and lacks markers for treatment prediction. This study investigated EGFR-induced epithelial-to-mesenchymal transition (EMT) as a central parameter in tumor progression and identified novel prognostic and therapeutic targets, and a candidate predictive marker for EGFR therapy response. Methods Transcriptomic profiles were analyzed by RNA sequencing (RNA-seq) following EGFR-mediated EMT in responsive human HNSCC cell lines. Exclusive genes were extracted via differentially expressed genes (DEGs) and a risk score was determined through forward feature selection and Cox regression models in HNSCC cohorts. Functional characterization of selected prognostic genes was conducted in 2D and 3D cellular models, and findings were validated by immunohistochemistry in primary HNSCC. Results An EGFR-mediated EMT gene signature composed of n = 171 genes was identified in responsive cell lines and transferred to the TCGA-HNSCC cohort. A 5-gene risk score comprising DDIT4, FADD, ITGB4, NCEH1, and TIMP1 prognosticated overall survival (OS) in TCGA and was confirmed in independent HNSCC cohorts. The EGFR-mediated EMT signature was distinct from EMT hallmark and partial EMT (pEMT) meta-programs with a differing enrichment pattern in single malignant cells. Molecular characterization showed that ITGB4 was upregulated in primary tumors and metastases compared to normal mucosa and correlated with EGFR/MAPK activity in tumor bulk and single malignant cells. Preferential localization of ITGB4 together with its ligand laminin 5 at tumor-stroma interfaces correlated with increased tumor budding in primary HNSCC tissue sections. In vitro, ITGB4 knock-down reduced EGFR-mediated migration and invasion and ITGB4-antagonizing antibody ASC8 impaired 2D and 3D invasion. Furthermore, a logistic regression model defined ITGB4 as a predictive marker of progression-free survival in response to Cetuximab in recurrent metastatic HNSCC patients. Conclusions EGFR-mediated EMT conveyed through MAPK activation contributes to HNSCC progression upon induction of migration and invasion. A 5-gene risk score based on a novel EGFR-mediated EMT signature prognosticated survival of HNSCC patients and determined ITGB4 as potential therapeutic and predictive target in patients with strong EGFR-mediated EMT.
Facts and Hopes on the Use of Artificial Intelligence for Predictive Immunotherapy Biomarkers in Cancer
Authors: Narmin Ghaffari Laleh, Marta Ligero, Raquel Perez-Lopez, Jakob Nikolas Kather
Journal: Clinical Cancer Research (2022)

Immunotherapy by immune checkpoint inhibitors has become a standard treatment strategy for many types of solid tumors. However, the majority of patients with cancer will not respond, and predicting response to this therapy is still a challenge. Artificial intelligence (AI) methods can extract meaningful information from complex data, such as image data. In clinical routine, radiology or histopathology images are ubiquitously available. AI has been used to predict the response to immunotherapy from radiology or histopathology images, either directly or indirectly via surrogate markers. While none of these methods are currently used in clinical routine, academic and commercial developments are pointing toward potential clinical adoption in the near future. Here, we summarize the state of the art in AI-based image biomarkers for immunotherapy response based on radiology and histopathology images. We point out limitations, caveats, and pitfalls, including biases, generalizability, and explainability, which are relevant for researchers and health care providers alike, and outline key clinical use cases of this new class of predictive biomarkers.
Isolation of viable monkeypox virus from anal and urethral swabs, Italy, May to July 2022
Authors: Davide Moschese, Giacomo Pozza, Davide Mileto, Andrea Giacomelli, Miriam Cutrera, Maria Vittoria Cossu, Maddalena Matone, Martina Beltrami, Federica Salari, Spinello Antinori, Alessandra Lombardi, Giuliano Rizzardini
Journal: Eurosurveillance (2022)

Anal and urethral samples from confirmed cases of monkeypox were screened for monkeypox virus (MPXV) by real-time PCR. Isolation of the virus was subsequently attempted in cell culture. Actively-replicating virus was demonstrated in 13 of 18 and 11 of 15 PCR-positive anal and urethral swabs, respectively, collected within 7 days from symptoms onset. Two asymptomatic secondary cases had detectable MPXV genetic material in urethral secretion and for one, MPXV was successfully isolated, supporting a potential MPXV sexual transmission hypothesis.
Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial
Authors: Paul DiSilvestro, Susana Banerjee, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander, Alla Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Amit Oza, Antonio González-Martín, Carol Aghajanian, William Bradley, Cara Mathews, Joyce Liu, John McNamara, Elizabeth S. Lowe, Mei-Lin Ah-See, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2022)

In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting.This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up.The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups.Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.
Nicotinamide riboside and pterostilbene reduces markers of hepatic inflammation in NAFLD: A double‐blind, placebo‐controlled clinical trial
Authors: Ryan W. Dellinger, Holly E. Holmes, Tina Hu‐Seliger, Rodney W. Butt, Stephen A. Harrison, Dariush Mozaffarian, Oliver Chen, Leonard Guarente
Journal: Hepatology (2022)

Background and Aims: The prevalence of NAFLD is increasing globally and on a path to becoming the most frequent cause of chronic liver disease. Strategies for the prevention and treatment of NAFLD are urgently needed. Approach and Results: A 6‐month prospective, randomized, double‐blind, placebo‐controlled clinical trial was conducted to assess the efficacy of daily NRPT (commercially known as Basis, a combination of nicotinamide riboside and pterostilbene) supplementation in 111 adults with NAFLD. The study consisted of three arms: placebo, recommended daily dose of NRPT (NRPT 1×), and a double dose of NRPT (NRPT 2×). NRPT appeared safe and well tolerated. At the end of the study, no significant change was seen in the primary endpoint of hepatic fat fraction with respect to placebo. However, among prespecified secondary outcomes, a time‐dependent decrease in the circulating levels of the liver enzymes alanine aminotransferase (ALT) and gamma‐glutamyltransferase (GGT) was observed in the NRPT 1× group, and this decrease was significant with respect to placebo. Furthermore, a significant decrease in the circulating levels of the toxic lipid ceramide 14:0 was also observed in the NRPT 1× group versus placebo, and this decrease was associated with a decrease in ALT in individuals of this group. A dose‐dependent effect was not observed with respect to ALT, GGT, or ceramide 14:0 in the NRPT 2× group. Conclusions: This study demonstrates that NRPT at the recommended dose is safe and may hold promise in lowering markers of hepatic inflammation in patients with NAFLD.
Genetics of the human microglia regulome refines Alzheimer’s disease risk loci
Authors: Roman Kosoy, John F. Fullard, Biao Zeng, Jaroslav Bendl, Pengfei Dong, Samir Rahman, Steven P. Kleopoulos, Zhiping Shao, Kiran Girdhar, Jack Humphrey, Katia de Paiva Lopes, Alexander W. Charney, Brian H. Kopell, Towfique Raj, David Bennett, Christopher P. Kellner, Vahram Haroutunian, Gabriel E. Hoffman, Panos Roussos
Journal: Nature Genetics (2022)
Non‐small cell lung cancer in China
Authors: Peixin Chen, Yunhuan Liu, Yaokai Wen, Caicun Zhou
Journal: Cancer Communications (2022)

In China, lung cancer is a primary cancer type with high incidence and mortality. Risk factors for lung cancer include tobacco use, family history, radiation exposure, and the presence of chronic lung diseases. Most early-stage non-small cell lung cancer (NSCLC) patients miss the optimal timing for treatment due to the lack of clinical presentations. Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China. The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC, thus prolonging survival in patients with positive drivers. In the exploration of immune escape mechanisms, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China. In the Chinese Society of Clinical Oncology's guidelines for NSCLC, maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy. Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC. In this review, we summarized recent advances in NSCLC in China in terms of epidemiology, biology, molecular pathology, pathogenesis, screening, diagnosis, targeted therapy, and immunotherapy.
A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries
Authors: Daren K. Heyland, Lucy Wibbenmeyer, Jonathan Pollack, Bruce Friedman, Alexis F. Turgeon, Niknam Eshraghi, Marc G. Jeschke, Sylvain Bélisle, Daisy Grau, Samuel Mandell, Sai R. Velamuri, Gabriel Hundeshagen, Naiem Moiemen, Kayvan Shokrollahi, Kevin Foster, Fredrik Huss, Declan Collins, Alisa Savetamal, Jennifer M. Gurney, Nadia Depetris, Christian Stoppe, Luis Ortiz-Reyes, Dominique Garrel, Andrew G. Day
Journal: New England Journal of Medicine (2022)

Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation.
Lung Cancer Absolute Risk Models for Mortality in an Asian Population using the China Kadoorie Biobank
Authors: Matthew T Warkentin, Martin C Tammemägi, Osvaldo Espin-Garcia, Sanjeev Budhathoki, Geoffrey Liu, Rayjean J Hung
Journal: JNCI Journal of the National Cancer Institute (2022)

Lung cancer is the leading cause of cancer mortality globally. Early detection through risk-based screening can markedly improve prognosis. However, most risk models were developed in North American cohorts of smokers, whereas less is known about risk profiles for never-smokers, which represent a growing proportion of lung cancers, particularly in Asian populations.Based on the China Kadoorie Biobank, a population-based prospective cohort of 512 639 adults with up to 12 years of follow-up, we built Asian Lung Cancer Absolute Risk Models (ALARM) for lung cancer mortality using flexible parametric survival models, separately for never and ever-smokers, accounting for competing risks of mortality. Model performance was evaluated in a 25% hold-out test set using the time-dependent area under the curve and by comparing model-predicted and observed risks for calibration.Predictors assessed in the never-smoker lung cancer mortality model were demographics, body mass index, lung function, history of emphysema or bronchitis, personal or family history of cancer, passive smoking, and indoor air pollution. The ever-smoker model additionally assessed smoking history. The 5-year areas under the curve in the test set were 0.77 (95% confidence interval = 0.73 to 0.80) and 0.81 (95% confidence interval = 0.79 to 0.84) for ALARM-never-smokers and ALARM-ever smokers, respectively. The maximum 5-year risk for never and ever-smokers was 2.6% and 12.7%, respectively.This study is among the first to develop risk models specifically for Asian populations separately for never and ever-smokers. Our models accurately identify Asians at high risk of lung cancer death and may identify those with risks exceeding common eligibility thresholds who may benefit from screening.